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Letters to the Editor

Effect of Mycophenolate Mofetil Dosing on Antibody Response to SARS-CoV-2 Vaccination in Heart and Lung Transplant Recipients

Mitchell, Jonathan MBBS1; Chiang, Teresa P-Y. MD, MPH1; Alejo, Jennifer L. MD1; Chang, Amy MD1; Abedon, Aura T. BS1; Avery, Robin K. MD2; Tobian, Aaron A. R. MD, PhD3; Massie, Allan B. PhD1,4; Levan, Macey L. JD, PhD1,5; Warren, Daniel S. PhD1; Garonzik-Wang, Jacqueline M. MD, PhD6; Segev, Dorry L. MD, PhD1,4; Werbel, William A. MD2

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doi: 10.1097/TP.0000000000004090
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Solid organ transplant recipients (SOTRs) demonstrate variable antibody responses after 2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine.1 Mycophenolate mofetil (MMF) use is associated with poor immunogenicity in SOTRs, but limited data exist on heart and lung transplant recipients (HLTRs). An increased risk of breakthrough infection in SOTRs2 has prompted interest in other methods to augment immune protection in this population, such as targeted immunosuppression reduction. This study assesses the effect of cumulative daily dose of MMF on antispike antibody titers after 2 doses of a SARS-CoV-2 mRNA vaccine in HLTRs.

HLTRs without a previously confirmed coronavirus disease 2019 infection (N = 212) were recruited as previously described.1 Immunosuppression regimens were self-reported, and participants were stratified into 4 groups based on reported total daily dose of MMF: zero MMF, low dose (<1000 mg/d), moderate dose (1000–2000 mg/d), and high dose (≥2000 mg/d). Patients receiving mycophenolic acid were excluded. Antispike antibody testing was performed at 1, 3, and 6 mo after dose 2 using commercially available assays, as previously described.1,3 The study was approved by the Johns Hopkins Institutional Review Board.

Clinical characteristics were compared using Wilcoxon rank-sum test for continuous and Fisher exact test for categorical variables. Multivariable Poisson regression with robust SE was used to estimate the risk of a negative antibody response associated with the MMF dose categories, adjusting for age, sex, vaccine type (mRNA-1273 versus BNT162b2), time since transplant, and steroid use. Analyses were performed using Stata 15.1/SE for Windows (College Station, TX).

At vaccination, 94 (44.3%) HLTRs reported receiving no MMF, 33 (15.6%) reported low-dose, 54 (25.7%) reported moderate-dose, and 31 (14.8%) reported high-dose regimens (Table 1). After adjustment, the risk of negative response in the low dose was comparable with that in the zero MMF group (risk ratio = 0.651.152.05; P = 0.63). However, the moderate- and high-dose groups had >2-fold higher risk of negative antibody response (risk ratio = 1.34 2.043.10 and 1.83 2.774.21, respectively; P < 0.01).

TABLE 1. - Demographics of heart and lung transplant recipients based on daily MMF dose category
Factor Zero MMF Low<1000 mg/d Moderate1000–1999 mg High≥2000 mg P
N 94 33 54 31
Vaccine series 0.66
 BNT162b2 49 (52.1%) 18 (54.5%) 30 (55.6%) 20 (64.5%)
 mRNA-1273 45 (47.9%) 15 (45.5%) 24 (44.4%) 11 (35.5%)
Age, median (IQR) 58.5 (41.9–68.9) 66.2 (50.8–70.2) 65.4 (48.5–70.3) 59.1 (41.2–66.4) 0.26
Sex 0.88
 Male 45 (47.9%) 16 (48.5%) 25 (46.3%) 17 (54.8%)
 Female 48 (51.1%) 17 (51.5%) 29 (53.7%) 14 (45.2%)
 Other 1 (1.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Years since transplant at dose 1, median (IQR) 6.6 (2.7–11.2) 5.5 (3.0–10.7) 5.2 (2.6–9.8) 4.3 (2.8–11.0) 0.64
History of rejectiona 5 (5.61%) 0 (0%) 1 (1.81%) 1 (3.33%) 0.51
Organ transplanted 0.049
 Lung 36 (38.3%) 23 (69.7%) 22 (40.7%) 13 (41.9%)
 Heart 55 (58.5%) 10 (30.3%) 32 (59.3%) 18 (58.1%)
 Heart and lung 3 (3.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Azathioprine 15 (16.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) <0.001
Calcineurin inhibitor 92 (97.9%) 30 (90.9%) 53 (98.1%) 28 (90.3%) 0.081
Tacrolimus 84 (89.4%) 28 (84.8%) 52 (96.3%) 27 (87.1%) 0.23
Steroids 58 (61.7%) 24 (72.7%) 25 (46.3%) 17 (54.8%) 0.094
mTOR inhibitor 42 (44.7%) 4 (12.1%) 3 (5.6%) 4 (12.9%) <0.001
Triple immunosuppressionb 0 (0.0%) 21 (63.6%) 25 (46.3%) 16 (51.6%) <0.001
aHistory of rejection in the 6 mo preceding vaccination.
bTriple immunosuppression consisted of any combination of MMF, calcineurin inhibitor, steroid, azathioprine, or mTOR inhibitor.
IQR, interquartile range; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin.

In this study of the effect of MMF dosing on antibody response to mRNA vaccination against SARS-CoV-2 in HLTRs, an MMF dose of >1000 mg/d was associated with increased risk of negative antibody response after a 2-dose SARS-CoV-2 mRNA vaccine series. Though the association of MMF use with poor antibody responses to SARS-CoV-2 vaccination in HLTRs has been previously reported,4 this is the first study to delineate the effect of MMF dosing on the antibody response in this population. There was a possibility for recall bias, as MMF doses were self-reported. Data regarding changes to MMF dose leading up to vaccination were unavailable. Additionally, although antibodies to the S1/receptor-binding domain are correlated with plasma neutralizing activity,5 neutralizing titers were not formally assessed.

In conclusion, higher MMF doses increase the risk of a negative antibody response to the 2-dose mRNA vaccine series in HLTRs. These findings may help guide approaches to third and booster doses, variant-specific next-generation vaccines, and the potential role for transient immunosuppression reduction strategies in ongoing trials where appropriate.

ACKNOWLEDGMENTS

The authors thank the participants of the Johns Hopkins transplant vaccine study, without whom this work would be impossible. They also thank the Johns Hopkins transplant vaccine study team, including Brian Boyarsky, MD, PhD; Mayan Teles, BS; Carolyn Sidoti, BS; Michael T. Ou, BS; Ross S. Greenberg, BA; Jake A. Ruddy, BS; Muhammad Asad Munir, MBBS; Michelle R. Krach, MS; and Iulia Barbur, BSE. They also thank Andrew H. Karaba, MD, PhD, and Ms Yolanda Eby for project support and guidance.

REFERENCES

1. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204–2206.
2. Qin CX, Moore LW, Anjan S, et al. Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients. Transplantation. 2021;105:e265–e266.
3. Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series. Ann Intern Med. 2021;174:1330–1332.
4. Hallett AM, Greenberg RS, Boyarsky BJ, et al. SARS-CoV-2 messenger RNA vaccine antibody response and reactogenicity in heart and lung transplant recipients. J Heart Lung Transplant. 2021;40:1579–1588.
5. Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27:1205–1211.
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